Biphenyl vasopressin agonists

ABSTRACT

A compound of the formulae (I) or (II): 
                         
wherein:
     Y is a moiety selected from NR or —(CH 2 ) n ;   wherein R is hydrogen or (C 1 –C 6 ) lower alkyl,   and n is 1;   
                         
represents:
         (1) a phenyl ring optionally substituted with one or two substituents selected, independently, from the group comprising hydrogen, (C 1 –C 6 ) lower alkyl, halogen, cyano, CF 3 , hydroxy, (C 1 –C 6 ) lower alkoxy, (C 1 –C 6 ) lower alkoxy carbonyl, carboxy, —CONH 2 , —CONH[(C 1 –C 6 ) lower alkyl], —CON[(C 1 –C 6 ) lower alkyl] 2 ; or   (2) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C 1 –C 6 ) lower alkyl, halogen or (C 1 –C 6 ) lower alkoxy;       
                         
represents:
         (1) a phenyl ring optionally substituted with one or two substituents selected, independently, from the group comprising hydrogen, (C 1 –C 6 ) lower alkyl, halogen, cyano, CF 3 , hydroxy, (C 1 –C 6 ) lower alkoxy, or (C 1 –C 6 ) lower alkoxy carbonyl, carboxy, —CONH 2 , —CONH[(C 1 –C 6 ) lower alkyl], —CON[(C 1 –C 6 ) lower alkyl] 2 ; or   (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C 1 –C 6 ) lower alkyl, (C 1 –C 6 ) lower alkoxy, or halogen; or   (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C 1 –C 6 ) lower alkyl, halogen, or (C 1 –C 6 ) lower alkoxy;       
                         
represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur atom, optionally substituted by (C 1 –C 6 ) lower alkyl, halogen, or (C 1 –C 6 ) lower alkoxy;
         R 1  is a moiety of the formula       
                         
and R 2 , R 3 , R 7 , R 8  and R 9  are, independently, selected from a group consisting of hydrogen, (C 1 –C 3 ) lower alkyl, OCH 3 , halogen, CF 3 , —SCH 3 , OCF 3 , SCF 3 , or CN;
 
or a pharmaceutically acceptable salt, or pro-drug form thereof.

This application is a divisional application of U.S. patent applicationSer. No. 10/121,156, filed Apr. 11, 2002, which claims the benefit ofU.S. Provisional Provisional Application Ser. No. 60/283,263, filed onApr. 12, 2001.

This invention concerns biphenyls which act as vasopressin V₂ agonists,as well as methods of treatment and pharmaceutical compositionsutilizing these compounds.

BACKGROUND OF THE INVENTION

Vasopressin plays a vital role in the conservation of water byconcentrating the urine in the collecting ducts of the kidney. Thecollecting ducts of the kidney are relatively impermeable to waterwithout the presence of vasopressin at the receptors and therefore, thehypotonic fluid formed after filtering through the glomeruli, passingthe proximal convoluted tubule, the loops of Henle, and the distalconvoluted tubules, will be excreted as dilute urine. However, duringdehydration, volume depletion or blood loss, vasopressin is releasedfrom the brain and activates the vasopressin V₂ receptors in thecollecting ducts of the kidney rendering the ducts very permeable towater; hence water is reabsorbed and a concentrated urine is excreted.Aquaporins (water channel membrane proteins) play a major role in thisintricate process (for a review on mammalian aquaporins, see Beitz andSchultz, Current Medicinal Chemistry, 6, 457–467 (1999)). In patientsand animals with central or neurogenic diabetes insipidus, the synthesisof vasopressin in the brain is defective and therefore, they producevery little or no vasopressin, but their vasopressin receptors in thekidneys are normal. Because they cannot concentrate the urine, they mayproduce as much as 10 times the urine volumes of their healthycounterparts and are very sensitive to the action of vasopressin andvasopressin V₂ agonists. Vasopressin and desmopressin,(1-desamino-8D-arginine vasopressin) which is a peptide analog of thenatural vasopressin, are being used in patients with central diabetesinsipidus. Vasopressin V₂ agonists are also useful for the treatment ofnocturnal enuresis, nocturia, urinary incontinence and temporary delayof urination, whenever desirable.

Vasopressin, through activation of its V_(1a) receptors, exertsvasoconstricting effects so as to raise blood pressure. A vasopressinV_(1a) receptor antagonist will counteract this effect. Vasopressin andvasopressin-like agonists cause release factor VIII and von Willebrandfactor from intracellular stores, so they are useful for the treatmentof bleeding disorders, such as hemophilia. Vasopressin andvasopressin-like agonists also release tissue-type plasminogen activator(t-PA) into the blood circulation so they are useful in dissolving bloodclots such as in patients with myocardial infarction and otherthromboembolic disorders (Jackson, “Vasopressin and other agentsaffecting the renal conservation of water”, in Goodman and Gilman, ThePharmacological Basis of Therapeutics, 9th ed., Hadman, Limbird,Molinoff, Ruddon and Gilman Eds., McGraw-Hill, New York, pp. 715–731(1996); Lethagen, Ann. Hematol. 69, 173–180 (1994); Cash et al., Brit.J. Haematol., 27, 363–364 (1974); David, Regulatory Peptides, 45,311–317 (1993); Burggraaf et al., Cli. Sci., 86, 497–503 (1994)).

Non-peptidic vasopressin antagonists have recently been disclosed.Albright et al. describe tricyclic azepines as vasopressin antagonistsor vasopressin and oxytocin antagonists in U.S. Pat. No. 5,516,774(1996), U.S. Pat. No. 5,532,235 (1996), U.S. Pat. No. 5,536,718, U.S.Pat. No. 5,610,156 (1997), U.S. Pat. No. 5,612,334 (1997), U.S. Pat. No.5,624,923 (1997), U.S. Pat. No. 5,654,297 (1997), U.S. Pat. No.5,686,445 (1997), U.S. Pat. No. 5,693,635 (1997), U.S. Pat. No.5,696,112 (1997), U.S. Pat. No. 5,700,796 (1997), U.S. Pat. No.5,719,278 (1998), U.S. Pat. No. 5,733,905 (1998), U.S. Pat. No.5,736,538 (1998), U.S. Pat. No. 5,736,540 (1998), U.S. Pat. No.5,739,128 (1998), U.S. Pat. No. 5,747,487 (1998), U.S. Pat. No.5,753,648 (1998), U.S. Pat. No. 5,760,031 (1998), U.S. Pat. No.5,780,471 (1998); tetrahydrobenzodiazepine derivatives as vasopressinantagonists are disclosed in J.P. 0801460-A (1996); Ogawa et al.,disclose benzoheterocyclic derivatives as vasopressin and oxytocinantagonists, and as vasopressin agonists in WO 9534540-A; Ogawa et al.disclose benzazepine derivatives with anti-vasopressin activity,oxytocin antagonistic activity and vasopressin agonist activity, usefulas vasopressin antagonists, vasopressin agonists and oxytocinantagonists in WO 97/22951 (1997) and U.S. Pat. No. 6,096,736 (2000);and Venkatesan et al., disclose tricyclic benzazepine derivatives asvasopressin and oxytocin antagonists in U.S. Pat. No. 5,521,173 (1996).Ohtahe et al. disclose ocular tension lowering agents and phosphoricester derivatives exhibiting vasopressin V₁ receptor antagonism in WO99/65525 (1999); and Hoekstra et al. disclose tricyclic benzodiazepinesuseful as vasopressin receptor antagonists for treating conditionsinvolving increased vascular resistance and cardiac insufficiency in WO00/43398 (2000).

Albright et al., disclose a subset of tricyclic dibenzodiazepines,pyrrolo benzodiazepines and pyrrolo pyridodiazepines related to thepresent application, as V₁ and/or V₂ vasopressin receptor antagonistsand oxytocin receptor antagonists in U.S. Pat. No. 5,849,735 (1998) andWO 96/22282 A1 (1996), inter alia.

Albright et al., disclose a subset of tricyclic benzazepines as V₁and/or V₂ vasopressin receptor antagonists and oxytocin receptorantagonists in U.S. Pat. No. 5,532,235 (1996).

Venkatesan et al. also teach a subset of tricyclic benzazepines withvasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,521,173(1996), WO 96/22292 (1996), and U.S. Pat. No. 5,780,471 (1998).

Albright et al., also broadly describe a subset of bicyclic azepines asV₁ and/or V₂ vasopressin receptor antagonists and oxytocin receptorantagonists in U.S. Pat. No. 5,696,112 (1997), and WO 96/22294.

SUMMARY OF THE INVENTION

This invention relates to novel and known compounds selected from thoseof formula (I) or (II):

wherein:

-   Y is a moiety selected from NR or —(CH₂)_(n);-   wherein R is hydrogen or (C₁–C₆) lower alkyl,-   and n is 1;

represents (1) a phenyl ring optionally substituted with one or twosubstituents selected, independently, from the group comprisinghydrogen, (C₁–C₆) lower alkyl, halogen, cyano, CF₃, hydroxy, (C₁–C₆)lower alkoxy, (C₁–C₆) lower alkoxy carbonyl, carboxy, —CONH₂,—CONH[(C₁–C₆) lower alkyl], —CON[(C₁–C₆) lower alkyl]₂;

-   or (2) a 6-membered aromatic (unsaturated) heterocyclic ring having    one nitrogen atom, optionally substituted by (C₁–C₆) lower alkyl,    halogen or (C₁–C₆) lower alkoxy;

represents (1) a a phenyl ring optionally substituted with one or twosubstituents selected, independently, from the group comprisinghydrogen, (C₁–C₆) lower alkyl, halogen, cyano, CF₃, hydroxy, (C₁–C₆)lower alkoxy, or (C₁–C₆) lower alkoxy carbonyl, carboxy, —CONH₂,—CONH[(C₁–C₆) lower alkyl], —CON[,(C₁–C₆) lower alkyl]₂;

-   or (2) a 5-membered aromatic (unsaturated) heterocyclic ring having    one nitrogen atom, optionally substituted by (C₁–C₆) lower alkyl,    (C₁–C₆) lower alkoxy, or halogen;-   or (3) a 6-membered aromatic (unsaturated) heterocyclic ring having    one nitrogen atom, optionally substituted by (C₁–C₆) lower alkyl,    halogen, or (C₁–C₆) lower alkoxy;

represents a 5-membered aromatic (unsaturated) heterocyclic ring havingone sulfur atom, optionally substituted by (C₁–C₆) lower alkyl, halogen,or (C₁–C₆) lower alkoxy;

-   R₁ is a moiety of the formula

wherein Ar is a moiety:

R₄ is the moiety

and R₂, R₇, R₈ and R₉ are, independently, selected from a groupconsisting of hydrogen, (C₁–C₃) lower alkyl, OCH₃, halogen, CF₃, SCH₃,OCF₃, SCF₃, or CN;or a pharmaceutically acceptable salt, or pro-drug form thereof.

One subset of compounds of this invention comprises those of theformulae:

wherein:

R₃ and R₅ are independently selected from H, C₁–C₆ alkyl, halogen,cyano, CF₃, hydroxy, C₁–C₆ alkoxy, C₁–C₆ alkoxy carbonyl, carboxy,—CONH₂, —CONH[C₁–C₆ alkyl], —CON[C₁–C₆ alkyl]₂;

R₂, R₇, R₈ and R₉ are each, independently, selected from the group ofhydrogen, C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃, or CN; and

R₁₀ is a group selected from C₁–C₆ alkyl, halogen, or C₁–C₆ alkoxy;

or a pharmaceutically acceptable salt or prodrug form thereof.

Another group of compounds of this invention comprises those of theformulae:

wherein:

R is hydrogen or C₁–C₆ alkyl;

R₃ and R₅ are independently selected from H, C₁–C₆ alkyl, halogen,cyano, CF₃, hydroxy, C₁–C₆ alkoxy, C₁–C₆ alkoxy carbonyl, carboxy,—CONH₂, —CONH[C₁–C₆ alkyl], —CON[C₁–C₆ alkyl]₂;

R₂, R₇, R₈ and R₉ are each, independently, selected from the group ofhydrogen, C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃, or CN; and

R₁₀ is a group selected from C₁–C₆ alkyl, halogen, or C₁–C₆ alkoxy;

or a pharmaceutically acceptable salt or prodrug form thereof.

Another group of compounds of this invention comprise those of theformulae:

wherein:

R₂, R₇, R₈ and R₉ are each, independently, selected from the group ofhydrogen, C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃, or CN; and

R₁₁ and R₁₂ are independently selected from C₁–C₆ alkyl, halogen, orC₁–C₆ alkoxy;

or a pharmaceutically acceptable salt or prodrug form thereof.

A further group of compounds of this invention comprises those of theformulae:

wherein:

R₂, R₇, R₈ and R₉ are each, independently, selected from the group ofhydrogen, C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃, or CN;

R₁₀ is a group selected from C₁–C₆ alkyl, halogen, or C₁–C₆ alkoxy; and

R₁₃ is C₁–C₆ alkyl, halogen or C₁–C₆ alkoxy;

or a pharmaceutically acceptable salt or prodrug form thereof.

A separate subgroup of compounds of this invention includes those of theformulae:

wherein:

R is hydrogen or C₁–C₆ alkyl;

R₃, R₅, R_(3′), and R_(5′) are independently selected from H, C₁–C₆alkyl, halogen, cyano, CF₃, hydroxy, C₁–C₆ alkoxy, C₁–C₆ alkoxycarbonyl, carboxy, —CONH₂, —CONH[C₁–C₆ alkyl], —CON[C₁–C₆ alkyl]₂;

R₂, R₇, R₈ and R₉ are each, independently, selected from the group ofhydrogen, C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃, or CN; and

or a pharmaceutically acceptable salt or prodrug form thereof.

As used herein the term “lower”, as used in relation to alkoxy or alkyl,is understood to refer to those groups having from 1 to 6 carbon atoms.Halogen refers to fluorine, chlorine, bromine or iodine.

Among the preferred compounds of this invention are:

EXAMPLE 1(2′-Methoxy-[1,1′-biphenyl]-4-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanoneEXAMPLE 2(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(3′-methyl-[1,1′-biphenyl]-4-yl)-methanoneEXAMPLE 3(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4′-methoxy-[1,1′-biphenyl]-4-yl)-methanoneEXAMPLE 4[1,1′-Biphenyl]-4-yl-(5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanoneEXAMPLE 5[1,1′-Biphenyl]-4-yl-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanoneEXAMPLE 6[1,1′-Biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanoneEXAMPLE 7[1,1′-Biphenyl]-4-yl-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanoneEXAMPLE 8[1,1′-Biphenyl]-4-yl-(5,6,7,8-tetrahydro-thieno[3,2-b]azepin-4-yl)-methanoneEXAMPLE 9(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(6-phenyl-pyridin-3-yl)-methanoneEXAMPLE 10(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(4′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)-methanoneEXAMPLE 11[1,1′-Biphenyl]-4-yl-(4H,10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone

It is understood by those practicing the art that some of the compoundsof this invention may contain one or more asymmetric centers and maythus give rise to stereoisomers and diastereomers. The present inventionincludes such stereoisomers and diastereomers; as well as the racemicand resolved, enantiomerically pure stereoisomers and pharmaceuticallyacceptable salts thereof, which possess the indicated activity.Stereoisomers may be obtained in pure form by standard procedures knownto those skilled in the art. It is also understood that this inventionencompasses all possible regioisomers, and mixtures thereof whichpossess the indicated activity. Such regioisomers may be obtained inpure form by standard separation procedures known to those skilled inthe art.

Also according to the present invention there is provided a method oftreating disorders which are remedied or alleviated by vasopressinreceptor agonist activity including, but not limited to, diabetesinsipidus, nocturnal enuresis, nocturia, urinary incontinence, orbleeding and coagulation disorders. This invention also provides amethod of inducing temporary delay of urination whenever desirable inhumans or other mammals. Each of these methods comprises administeringto a human or other mammal in need thereof an effective amount of acompound or a pharmaceutical composition of the invention.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a pharmaceutically effective amount of a compound ofthis invention in combination or association with a pharmaceuticallyacceptable carrier or excipient. In particular, the present inventionprovides a pharmaceutical composition which comprises an effectiveamount of a compound of this invention and a pharmaceutically acceptablecarrier. A pharmaceutically effective amount of a compound herein isunderstood to be at least the minimum amount which will provide adesirable result in inducing a temporary delay in urination or inremedying, inhibiting or alleviating the malady in question or providingrelief from its symptoms.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample, parenteral administration for patients suffering from heartfailure.

In order to obtain consistency of administration, it is preferred that acomposition of the invention is in the form of a unit dose. Suitableunit dose forms include tablets, capsules and powders in sachets orvials. Such unit dose forms may contain from 0.1 to 1000 mg of acompound of the invention and preferably from 2 to 50 mg. Still furtherpreferred unit dosage forms contain 5 to 25 mg of a compound of thepresent invention. The compounds of the present invention can beadministered orally at a dose range of about 0.01 to 100 mg/kg orpreferably at a dose range of 0.1 to 10 mg/kg. Such compositions may beadministered from 1 to 6 times a day, more usually from 1 to 4 times aday. The compositions of the invention may be formulated withconventional excipients, such as a filler, a disintegrating agent, abinder, a lubricant, a flavoring agent and the like. They are formulatedin conventional manner, for example, in a manner similar to that usedfor known antihypertensive agents, diuretics and β-blocking agents.

Also according to the present invention there are provided processes forproducing the compounds of the present invention.

PROCESS OF THE INVENTION

The compounds of the present invention of general formula (I) may beconveniently prepared according to the process shown in Scheme I.

Thus, a tricyclic azepine (diazepine) of formula (1) is treated with anappropriately substituted acylating agent such as an aroyl halide,preferably an appropriately substituted acyl chloride (bromide) offormula (2, J=COCl or COBr), in the presence of an inorganic base suchas potassium carbonate, or in the presence of an organic base such aspyridine, 4-(dimethylamino)pyridine, or a tertiary amine such astriethylamine or N,N-diisopropyl ethyl amine, in an aprotic solvent suchas dichloromethane, N,N-dimethylfornamide or tetrahydrofuran, attemperatures ranging from −5° C. to 50° C. to provide the desiredcompounds of general formula (I) wherein R₁ is defined hereinbefore.

Alternatively, the acylating species of formula (2) can be a mixedanhydride of the corresponding carboxylic acid, such as that prepared bytreating said acid with 2,4,6-trichlorobenzoyl chloride in an aproticorganic solvent such as dichloromethane according to the procedure ofInanaga et al., Bull. Chem. Soc. Jpn., 52, 1989 (1979). Treatment ofsaid mixed anhydride of general formula (2) with a tricyclic azepine(diazepine) of formula (1) in a solvent such as dichloromethane and inthe presence of an organic base such as 4-(dimethylamino)pyridine attemperatures ranging from 0° C. to the reflux temperature of thesolvent, yields the acylated derivative (I) of Scheme I.

The acylating intermediate of formula (2) is ultimately chosen on thebasis of its compatibility with the R₁ groups, and its reactivity withthe tricyclic azepine (diazepine) of formula (1).

Likewise, treatment of a bicyclic azepine of formula (3) underconditions similar to those described hereinbefore provides the desiredcompounds of general formula (II) wherein R₁ is defined hereinbefore, asshown in Scheme II.

The desired intermediates of formula (2) of Scheme I and II can beconveniently prepared by a process shown in Scheme III. Thus, anappropriately substituted aryl(heteroaryl)iodide (bromide, chloride, ortrifluoromethane sulfonate) of formula (4, wherein P is a carboxylicacid protecting group, preferably P=alkyl or benzyl, M=I, Br, Cl, OTf),A is CH or nitrogen, and R₂ is defined hereinbefore, is reacted with anaryl(heteroaryl)tri(alkyl)tin(IV) derivative of formula (5,W=Sn(trialkyl)₃, preferably Sn(n-Bu)₃) wherein R₇, R₈ and R₉ are definedhereinbefore, in the presence of a Pd(0) catalyst and in the presence orabsence of inorganic salts (e.g. LiCl), to provide the intermediateester (6). Subsequent unmasking of the carboxylic acid by hydrolysis,hydrogenolysis or similar methods known in the art, followed byactivation of the intermediate acid (7) provides the desired compoundsof formula (8) wherein A, R₂, R₇, R₈, and R₉ are hereinbefore defined,suitable for coupling with either the tricyclic azepine (diazepine) offormula (1), or with the bicyclic azepine of formula (3), respectively.

Alternatively, the desired intermediates of formula (6) of Scheme IIIcan be prepared by coupling of the iodide (bromide, chloride,trifluoromethanesulfonate) (4, M=I, Br Cl, or OTf) with an appropriatelysubstituted aryl(heteroaryl)boron derivative of formula (5, preferablyW=B(OH)₂) in the presence of a palladium catalyst such as palladium(II)acetate or tetrakis(triphenylphosphine)palladium(0) and an organic basesuch as triethylamine or an inorganic base such as sodium (potassium orcesium) carbonate with or without added tetrabutylammonium bromide(iodide), in a mixture of solvents such as toluene-ethanol-water,acetone-water, water or water-acetonitrile at temperatures ranging fromambient to the reflux temperature of the solvent (Suzuki, Pure & Appl.Chem. 66, 213–222 (1994); Badone et al., J. Org. Chem. 62, 7170–7173(1997); Wolfe et al., J. Am. Chem. Soc. 121, 9559 (1999); Shen, Tetr.Letters 38, 5575 (1997)). The exact conditions for the Suzuki couplingof (4) and the boronic acid intermediate are chosen on the basis of thenature of the substrate and the substituents.

The desired intermediates of formula (6) of Scheme III can be similarlyprepared from the bromide (4, M=Br) and the boronic acid (5) in asolvent such as dioxane, in the presence of potassium phosphate and aPd(0) catalyst.

Alternatively, a cross coupling reaction of an iodide (bromide,chloride, or trifluoromethane sulfonate) of formula (5, W=Br, Cl, I,OTf) with a bis(pinacolato)diboron [boronic acid, or trialkyl tin(IV)]derivative of formula (4, M=

B(OH)₂, or SnBu₃) yields the desired intermediate of formula (6) whichis converted to (I) or (II) in the manner of Scheme III.

The required appropriately substituted aryl(heteroaryl)halides offormula (4, M=Br or I) of Scheme III are either available commercially,or are known in the art or can be readily accessed in quantitativeyields and high purity by diazotization of the corresponding substitutedanilines (4, P=H, alkyl or benzyl, M=NH₂) followed by reaction of theintermediate diazonium salt with iodine and potassium iodide in aqueousacidic medium essentially according to the procedures of Street et al,.J. Med. Chem. 36, 1529 (1993) and Coffen et al., J. Org. Chem. 49, 296(1984) or with copper(I) bromide, respectively (March, Advanced OrganicChemistry, 3^(rd) Edn., p.647–648, John Wiley & Sons, New York (1985)).

Alternatively, the desired intermediates of formula (7, A=CH) of SchemeIII can be conveniently prepared as shown in Scheme IV by cross-couplingreaction of an appropriately substituted pinacolato borane of formula(11) wherein R₇, R₈ and R₉ are hereinbefore defined, with an aryltriflate of formula (12, Y=OTf) or an aryl halide of formula (12, Y=Br,I) wherein R₂ is defined hereinbefore, according to the generalprocedures of Ishiyama et al., Tetr. Lett. 38, 3447–3450 (1997) andGiroux et al. Tetr. Lett. 38, 3841–3844 (1997), followed by basic oracidic hydrolysis of the intermediate nitrile of formula (13) (cf.March, Advanced Organic Chemistry, 3^(rd) Edn., John Wiley & Sons, NewYork, p. 788 (1985)).

Alternatively, reaction of an iodide (bromide, ortrifluoromethanesulfonate) of formula (9, X=Br, I, or OTf) with abis(pinacolato)diboron [boronic acid or trialkyl tin(IV)] derivative offormula (12, Y=

B(OH)₂, or SnBu₃) yields the desired intermediate of formula (13) whichis converted to (7) in the manner of Scheme V.

The desired phenyl boronic esters of formula (11) of Scheme IV can beconveniently prepared by the palladium-catalyzed cross-coupling reactionof the pinacol ester of diboronic acid (10) with an appropriatelysubstituted aryl halide preferably a bromide or iodide (9, X=Br, I) oraryl triflate (9, X=OTf) according to the described procedures ofIshiyama et al., J. Org. Chem. 60, 7508–7510 (1995) and Giroux et al.,Tetr. Lett. 38, 3841–3844 (1997).

The desired compounds of formula (I) of Scheme III can be alternativelyprepared by a process shown in Scheme V.

Thus, a tricyclic azepine (diazepine) of formula (1) is treated with anappropriately substituted acylating agent such as a haloaroyl(heteroaroyl)halide, preferably aniodo(bromo)aroyl(heteroaroyl)chloride(bromide) of formula (14, J=COCl orCOBr; X=I, Br) wherein A and R₂ are hereinbefore defined using any ofthe procedures hereinbefore described, to provide the acylatedintermediate of general formula (15) of Scheme V. In analogous fashion abicyclic azepine of formula (3) is converted into the desired compoundsof formula (16) of Scheme V, using any of the procedures hereinbeforedescribed.

Alternatively, the acylating species of formula (14) can be a mixedanhydride of the corresponding carboxylic acid. Treatment of said mixedanhydride of general formula (14) with either a tricyclic azepine(diazepine) of formula (1) or a bicyclic azepine of formula (3)according to the procedure described hereinbefore, yields theintermediate acylated derivatives (15) and (16), respectively.

The acylating intermediate of formula (14) is ultimately chosen on thebasis of its compatibility with A and the R₂ group, and its reactivitywith the tricyclic azepine (diazepine) of formula (1) or the bicyclicazepine of formula (3), respectively.

A Stille coupling reaction of (15, X=I) or (16, X=I) with anappropriately substituted organotin reagent such as a trialkyltin(IV)derivative, preferably a tri-n-butyltin(IV) derivative of formula (5,W=SnBu₃) where R₇, R₈ and R₉ are hereinbefore defined, in the presenceof a catalyst such as tetrakis(triphenylphosphine)palladium(0) in anaprotic organic solvent such as toluene or N,N-dimethylformamide, attemperatures ranging from ambient to 150° C. (cf. Farina et al., J. Org.Chem, 59, 5905 (1994) and references cited therein) affords the desiredcompounds of formula (I) or (II) respectively, wherein

Y, A, R₂, R₇, R₈ and R₉ are as defined hereinbefore.

Alternatively, the reaction of a compound of formula (15, X=Cl, Br or I)or (16, X=Cl, Br or I) with an appropriately substitutedaryl(heteroaryl)boronic acid of formula (5, W=B(OH)₂) wherein A, R₂, R₇,R₈, and R₉ are hereinbefore defined, in a mixture of solvents such astoluene-ethanol-water, and in the presence of a Pd(0) catalyst and abase such as sodium carbonate, at temperatures ranging from ambient tothe reflux temperature of the solvent, yields the desired compounds offormula (I) or (II) respectively, wherein

Y, A, R₂, R₇, R₈, and R₉ are as defined hereinbefore.

The preferred substituted aroyl(heteroaroyl)chlorides(bromides) offormula (14) of Scheme V (X=I, Br; J=COCl or COBr) wherein A and R₂ areas defined hereinbefore, are either available commercially, or are knownin the art, or can be readily prepared by procedures analogous to thosein the literature for the known compounds.

The intermediates of formula (5, W=Sn(alkyl)₃, preferably alkyl=n-butyl)of Scheme V are either commercially available, or can be convenientlyprepared as shown in Scheme VI from the corresponding bromo startingmaterials of formula (17) wherein R₇, R₈, and R₉ are hereinbeforedefined, by first reacting them with n-butyl lithium followed byreaction of the intermediate lithiated species with a trialkyl(preferably trimethyl or tri-n-butyl)tin(IV) chloride.

The preferred substituted aryl(heteroaryl)boronic acids of formula (5,W=B(OH)₂) are either available commercially, or are known in the art, orcan be readily prepared by procedures analogous to those in theliterature for the known compounds.

Alternatively, as shown in Scheme VII, the appropriately substitutedaroyl(heteroaroyl)halides, preferably aroyl(heteroaroyl)chlorides offormula (18, J=COCl) where A and R₂ are hereinbefore defined, arereacted with a tricyclic azepine (diazepine) of formula (1) to providethe intermediate bromides of formula (19). Subsequent reaction of (19)with an hexa alkyl-di-tin (preferably hexa-n-butyl-di-tin(IV)) in thepresence of a Pd(0) catalyst such astetrakis(tri-phenylphosphine)palladium(0) and lithium chloride, providesthe stannane intermediate of formula (20). Further reaction of thetri-n-butyl tin(IV) derivative (20) with the appropriately substitutedaryl(heteroaryl)halide of formula (21, M=bromo or iodo) wherein R₇, R₈,and R₉ are hereinbefore defined, in the presence of a Pd(0) catalystsuch as tetrakis(triphenylphosphine)palladium(0), yields the desiredcompounds of formula (I) wherein

A, Y, R₂, R₇, R₈ and R₉ are defined hereinbefore.

The desired compounds of formula (II) of Scheme II wherein

A, R₂, R₇, R₈ and R₉ are defined hereinbefore, can be prepared inanalogous fashion by reacting a bicyclic azepine of formula (3) withintermediates of formula (18) and (21) according to Scheme VII above.

The subject compounds of the present invention were tested forbiological activity according to the following procedures.

Vasopressin V₂ Agonist Effects of Test Compounds in Normal ConsciousWater-Loaded Rats

Male or female normotensive Sprague-Dawley rats (Charles RiverLaboratories, Inc., Kingston, N.Y.) of 350–500 g body weight weresupplied with standard rodent diet (Purina Rodent Lab. Chow 5001) andwater ad libitum. On the day of test, rats were placed individually intometabolic cages equipped with devices to separate the feces from theurine and containers for collection of urine. A test compound or areference agent was given at an oral dose of 10 mg/Kg in a volume of 10mL/Kg. The vehicle used was 2.5% preboiled corn starch in 20%dimethylsulfoxide (DMSO). Thirty minutes after dosing the test compound,rats were gavaged with water at 30 mL/Kg into the stomach using afeeding needle. During the test, rats were not provided with water orfood. Urine was collected for four hours after dosing of the testcompound. At the end of four hours, urine volume was measured. Urinaryosmolality was determined using a Fiske One-Ten Osmometer (FiskeAssociates, Norwood, Mass., 02062) or an Advanced CRYOMATIC Osmometer,Model 3C2 (Advanced Instruments, Norwood, Mass.). Determinations of Na⁺,K⁺ and Cl⁻ ion were carried out using ion specific electrodes in aBeckman SYNCHRON ELISE Electrolyte System analyzer. The urinaryosmolality should increase proportionally. In the screening test, tworats were used for each compound. If the difference in the urine volumeof the two rats was greater than 50%, a third rat was used.

The results of this study are shown in Table 1.

TABLE 1 Urine Volume Urinary Osmolality Example (% decrease)^(a) (%increase)^(b) Rat Type^(c) 1 67 163 CD 2 27 33 CD 3 18 78 CD 4 56 151 CD5 22 26 CD 6 87 247 CD 7 70 189 CD 8 35 73 CD 9 62 156 CD 10 60 234 CD^(a)Percent decrease in urine volume vs control at a dose of 10 mg/Kg^(b)Percent increase in osmolality vs control at a dose of 10 mg/Kg^(c)Rat model used: Sprague-Dawley (CD)The following examples are presented to illustrate rather than limit thescope of the invention.

EXAMPLE 1(2′-Methoxy-[1,1′-biphenyl]-4-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

Step A. 2′-Methoxy-[1,1′-biphenyl]-4-carboxylic acid ethyl ester

A mixture of 4-bromo benzoic acid ethyl ester (2.7 mL, 16.5 mmol),2-methoxy boronic acid (2.5 g, 16.5 mmol) and sodium carbonate (7.7 g,72.6 mmol) in toluene: ethanol:water (75 mL:37 mL:37 mL), was flushedwith nitrogen for 1 hour. After addition of thetetrakis(triphenylphosphine)palladium(0) catalyst (0.96 g, 0.83 mmol),the reaction mixture was heated at 100° C. overnight. After cooling, themixture was filtered through Celite which was then rinsed with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brown oil.Purification of the residue by flash chromatography with a solventgradient from 25% to 50% dichloromethane in hexane provided the titlecompound (3.8 g, 89.9%) as a pale yellow oil.

¹H-NMR (DMSO-d₆, 400 MHz): δ 1.32 (t, 3H), 3.76 (s, 3H), 4.32 (q, 2H),7.02–7.06 (m, 1H), 7.12–7.14 (m, 1H), 7.31–7.33 (m, 1H), 7.36–7.40 (m,1H), 7.59–7.63 (m, 2H), 7.96–7.99 (m, 2H).

MS [EI, m/z]: 256 [M]⁺.

Anal. Calcd. for C₁₆H₁₆O₃: C, 74.98, H, 6.29. Found: C, 75.11, H, 6.71.

Step B. 2′-Methoxy-[1,1′-biphenyl]-4-carboxylic acid

A mixture of 2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid ethyl ester ofStep A (3.7 g, 14.4 mmol) in tetrahydrofuran (40 mL) and 1 N sodiumhydroxide (30 mL, 30 mmol) was heated at reflux overnight. Aftercooling, the reaction mixture was concentrated in vacuo, and the residuewas acidified with 2N hydrochloric acid to give a white solid which wascollected by filtration and dried under vacuum to provide the titlecompound (3.2 g, 97.4%) as a white solid, m.p. 250–253° C.

¹H-NMR (DMSO-d₆, 400 MHz): δ 3.78 (s, 3H), 7.04–7.08 (m, 1H), 7.13–7.16(m, 1H), 7.32–7.35 (m, 1H), 7.37–7.41 (m, 1H), 7.59–7.62 (m, 2H),7.96–7.99 (m, 2H), 12.92 (broad s, 1H).

MS [EI, m/z]: 228 [M]⁺.

Anal. Calcd. for C₁₄H₁₂O₃+0.01CH₂Cl₂+0.04C₄H₈O: C, 73.34, H, 5.39.Found: C, 72.74, H, 5.46.

Step C.(2′-Methoxy-[1,1′-biphenyl]-4-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

A suspension of 2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step B(1.0 g, 4.38 mmol) in thionyl chloride (6 mL) was heated at reflux for30 min. After cooling, the thionyl chloride was removed in vacuo. Theresidue was dissolved in toluene and concentrated in vacuo to give thecrude acid chloride as a yellow solid. The latter was then dissolved indichloromethane (10 mL) and the solution was slowly added to a solutionof 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.97 g, 5.27mmol) and N,N-diisopropylethyl amine (1.6 mL, 9.19 mmol) indichloromethane (30 mL). After stirring for 2 hours, the reaction wasquenched with water. The organic layer was washed with 1 N hydrochloricacid, 1 N sodium hydroxide and brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a yellow foam.Purification of the residue by flash chromatography using a solventgradient from 15% to 25% of ethyl acetate in hexane provided the titlecompound as a white foam which was crystallized by sonication from ethylacetate/hexane (1.4 g, 81.0%) to give a white solid m.p. 145–147° C.

¹H-NMR (DMSO-d₆, 400 MHz): δ 3.71 (s, 3H), 4.80–5.40 (broad s, 4H),5.92–5.93 (m, 1H), 5.95 (s, 1H), 6.82 (t, 1H), 6.96–7.00 (m, 2H), 7.08(d, 1H), 7.12–7.21 (m, 3H), 7.29–7.35 (m, 5H), 7.47–7.49 (m, 1H)

MS [(+) ESI, m/z]: 395 [M+H]⁺.

Anal. Calcd. for C₂₆H₂₂N₂O₂+0.08C₄H₈O₂: C, 78.73, H, 5.68, N, 6.98.Found: C, 78.47, H, 5.77, N, 7.00.

EXAMPLE 2(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(3′-methyl-[1,1′-biphenyl]-4-yl)-methanone

Step A. 3′-Methyl-[1,1′-biphenyl]-4-carboxylic acid ethyl ester

A mixture of 4-bromo benzoic acid ethyl ester (2.7 mL, 16.5 mmol),3-methyl phenylboronic acid (2.2 g, 16.2 mmol) and sodium carbonate (7.5g, 70.8 mmol) in toluene:ethanol:water (75 mL:37 mL:37 mL), was flushedwith nitrogen for 1 hour. After addition of thetetrakis(triphenylphosphine)palladium(0) catalyst (0.94 g, 0.81 mmol),the reaction was heated at 100° C. overnight. After cooling, the mixturewas filtered through Celite which was then washed with ethyl acetate.The organic layer was washed with water, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a brown oil.Purification of the residue by flash chromatography with a solventgradient from 25% to 50% of dichloromethane in hexane provided the titlecompound (3.4 g, 87.3%) as a colorless oil.

¹H-NMR (DMSO-d₆, 400 MHz): δ 1.34 (t, 3H), 2.39 (s, 3H), 4.34 (q, 2H),7.23–7.25 (m, 1H), 7.39 (t, 1H), 7.51–7.55 (m, 2H), 7.79–7.82 (m, 2H),8.01–8.04 (m, 2H).

MS [EI, m/z]: 240 [M]⁺.

Anal. Calcd. for C₁₆H₁₆O₂: C, 79.97, H, 6.71. Found: C, 79.54, H, 6.71.

Step B. 3′-Methyl-[1,1′-biphenyl]-4-carboxylic acid

A solution of 3′-methyl-[1.1′-biphenyl]-4-carboxylic acid ethyl ester ofStep A (3.3 g, 13.7 mmol) in tetrahydrofuran (40 mL) and 1 N sodiumhydroxide (27.5 mL, 27.5 mmol) was heated at reflux overnight. Aftercooling, the reaction was concentrated in vacuo. The residue wasacidified with 2N hydrochloric acid to yield a white solid which wascollected by filtration and dried under vacuum to provide the titlecompound (2.9 g, 99.7%) as a white solid, m.p. 198–200° C.

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.39 (s, 3H), 7.24 (d, 1H), 7.39 (t, 1H),7.51–7.56 (m, 2H), 7.77–7.80 (m, 2H), 8.00–8.03 (m, 2H), 12.96 (broad s,1H).

MS [EI, m/z]: 212 [M]⁺.

Anal. Calcd. for C₁₄H₂O₂: C, 79.22, H, 5.70. Found: C, 78.82, H, 5.87.

Step C.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(3′-methyl-[1,1′-biphenyl]-4-yl)-methanone

A suspension of 3′-methyl-[1,1′-biphenyl]-4-carboxylic acid of Step B(0.50 g, 2.36 mmol) in thionyl chloride (3 mL) was heated at reflux for30 minutes. After cooling, the thionyl chloride was removed in vacuo.The residue was dissolved in toluene and concentrated in vacuo to givethe crude acid chloride as a yellow oil. The acid chloride was thendissolved in dichloromethane (5 mL) and slowly added to a solution ofthe 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.65 g, 3.53mmol) and N,N-diisopropylethyl amine (0.90 mL, 5.17 mmol) indichloromethane (15 mL). After stirring for 2 hours, the reaction wasquenched with water. The organic layer was washed with 1 N hydrochloricacid, 1 N sodium hydroxide and brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo to give a white foam. Purification ofthe residue by flash chromatography using a solvent gradient from 15% to25% of ethyl acetate in hexane gave a white foam which was crystallizedby sonication from ethyl acetate/hexane to provide the title compound(0.74 g, 82.8%) as a white solid, m.p. 128–130° C.

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.35 (s, 3H), 4.80–5.40 (broad s, 4H),5.93–5.95 (m, 1H), 5.97 (s, 1H), 6.85 (t, 1H), 6.96–6.98 (m, 1H), 7.12(t, 1H), 7.17–7.21 (m, 2H), 7.30–7.44 (m, 5H), 7.48–7.54 (m, 3H).

MS [EI, m/z]: 378 [M]⁺.

Anal. Calcd. for C₂₆H₂₂N₂O+0.10C₄H₈O₂: C, 81.88, H, 5.93, N, 7.23.Found: C, 81.54, H, 5.99, N, 7.29.

EXAMPLE 3(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4′-methoxy[1,1′-biphenyl]-4-yl)-methanone

Step A. 4′-Methoxy-[1,1′-biphenyl]-4-carboxylic acid ethyl ester

A mixture of 4-bromobenzoic acid ethyl ester (2.7 mL, 16.5 mmol),4-methoxy phenylboronic acid (2.5 g, 16.5 mmol) and sodium carbonate(7.7 g, 72.6 mmol) in toluene:ethanol:water (75 mL:37 mL:37 mL) wasflushed with nitrogen for 1 hour. After addition of thetetrakis(triphenylphosphine)palladium(0) catalyst (0.95 g, 0.82 mmol),the reaction was heated at 100° C. overnight. After cooling, the mixturewas filtered through Celite which was then washed with ethyl acetate.The organic layer was washed with water, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a brown solid.Purification of the residue by flash chromatography with a solventgradient from 25% to 50% of dichloromethane in hexane provided the titlecompound (4.05 g, 95.8%) as a pale yellow solid, m.p. 101–103° C.

¹H-NMR (DMSO-d₆, 400 MHz): δ 1.34 (t, 3H), 3.81 (s, 3H), 4.33 (q, 2H),7.05–7.07 (m, 2H), 7.69–7.71 (m, 2H), 7.77–7.79 (m, 2H), 7.98–8.01 (m,2H).

MS [EI, m/z]: 256 [M]⁺.

Anal. Calcd. for C₁₆H₁₆O₃: C, 74.98, H, 6.29. Found: C, 74.92, H, 6.16.

Step B. 4′-Methoxy-[1,1′-biphenyl]-4-carboxylic acid

A solution of the ester of Step A (3.9 g, 15.2 mmol) in tetrahydrofuran(50 mL) was treated with 1 N sodium hydroxide (31 mL, 31 mmol) and thenheated at reflux overnight. After cooling, the reaction mixture wasconcentrated in vacuo. The residue was acidified with 2N hydrochloricacid to give a white solid which was collected by filtration and driedunder vacuum to provide the title compound (3.4 g, 98.0%) as a whitesolid, m.p. 250–254° C.

¹H-NMR (DMSO-d₆, 400 MHz): δ 3.81 (s, 3H), 7.04–7.08 (m, 2H), 7.68–7.71(m, 2H), 7.73–7.77 (m, 2H), 7.98–8.01 (m, 2H), 12.91 (broad s, 1H).

MS [(−) ESI, m/z]: 227 [M−H]⁻.

Anal. Calcd. for C₁₄H₁₂O₃: C, 73.67, H, 5.30. Found: C, 73.11, H, 5.41.

Step C.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4′-methoxy-[1,1′-biphenyl]-4-yl)-methanone

A suspension of the carboxylic acid of Step B (1.0 g, 4.38 mmol) inthionyl chloride (6 mL) was heated at reflux for 1 hour. After cooling,the thionyl chloride was removed in vacuo. The residue was dissolved intoluene and concentrated in vacuo to give the crude acid chloride as alight brown solid. The acid chloride was then dissolved indichloromethane (10 mL) and slowly added to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.2 g, 6.52 mmol)and N,N-diisopropylethyl amine (1.7 mL, 9.76 mmol) in dichloromethane(25 mL). After stirring for 2 hours, the reaction was quenched withwater. The organic layer was washed with 1N hydrochloric acid, 1N sodiumhydroxide and brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a yellow foam. Purification of the residueby flash chromatography using a solvent gradient from 15% to 50% ofethyl acetate in hexane provided the title compound (1.5 g, 86.8%) as awhite solid, m.p. 187–189° C.

¹H-NMR (DMSO-d₆, 400 MHz): δ 3.76 (s, 3H), 4.80–5.40 (broad s, 4H),5.92–5.94 (m, 1H), 5.96 (s, 1H), 6.83 (t, 1H), 6.94–6.99 (m, 3H), 7.10(t, 1H), 7.15–7.19 (m, 1H), 7.32 (d, 2H), 7.47–7.49 (m, 3H), 7.55–7.58(m, 2H).

MS [(+) ESI, m/z]: 395 [M+H]⁺.

Anal. Calcd. for C₂₆H₂₂N₂O₂+0.20CH₂Cl₂: C, 76.48, H, 5.49, N, 6.81.Found: C, 76.10, H, 5.68, N, 6.87.

EXAMPLE 4[1,1′-Biphenyl]-4-yl-(5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone

To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (1.0g, 5.07 mmol) in N,N-dimethylformamide (10 mL) kept under nitrogen wasadded solid potassium carbonate (0.74 g, 5.35 mmol). The mixture wastreated dropwise with a solution of 4-biphenylcarbonyl chloride (1.4 g,6.46 mmol) in N,N-dimethylformamide (5 mL) and stirred at roomtemperature for 1 hour. The mixture was then diluted with water andextracted with ethyl acetate. The organic extracts were combined andwashed with 1N sodium hydroxide, dried over anhydrous sodium sulfate andevaporated to dryness to give a pink foam which was purified by flashchromatography. Elution with 25% ethyl acetate in hexane provided awhite foam which was redissolved in dichloromethane, concentrated invacuo to a foam, then crystallized by sonication from ethylacetate/hexane to give the title compound (1.28 g, 66.9%) as a whitesolid, m.p. 175–177° C.

¹H-NMR (DMSO-d₆, 400 MHz): δ 4.11 (d, 1H), 5.60 (d, 1H), 6.53–6.59 (m,1H), 6.68–6.70 (m, 1H), 6.72–6.78 (m, 1H), 7.04–7.09 (m, 1H), 7.20 (d,2H), 7.32–7.36 (m, 2H), 7.37–7.43 (m, 2H), 7.48–7.61 (m, 5H), 8.10–8.12(m, 1H), 9.62 (s, 1H).

MS [(+) ESI, m/z]: 378 [M+H]⁺.

Anal. Calcd. for C₂₅H₁₉N₃O+0.05C₄H₈O₂+0.05CH₂Cl₂: C, 78.55, H, 5.09, N,10.88. Found: C, 78.55, H, 4.90, N, 10.87.

EXAMPLE 5[1,1′-Biphenyl]-4-yl-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone

Sodium hydride (60% suspension, 0.10 g, 2.5 mmol) washed with hexane anddried under nitrogen, was suspended in dry N,N-dimethylformamide (15mL). Following addition of1,1′-biphenyl-4-yl-(5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanoneof Example 4 (0.76 g, 2.0 mmol), methyl iodide (0.15 mL, 2.4 mmol) wasadded. After stirring for 1 hour, the reaction was quenched with waterand extracted with dichloromethane The organic layers were dried overanhydrous sodium sulfate and concentrated in vacuo to give a yellowsolid. Purification of the residue by flash chromatography using asolvent gradient from 25% to 35% of ethyl acetate in hexane gave a whitefoam which was redissolved in dichloromethane, concentrated in vacuo toa foam, then crystallized by sonication from ethyl acetate/hexane toprovide the title compound (0.48 g, 61.3%) as a white solid, m.p.220–223° C.

¹H-NMR (DMSO-d₆, 400 MHz): δ 3.55 (s, 3H), 4.28–4.40 (broad m, 1H),5.70–5.85 (broad m, 1H), 6.88–6.97 (m, 2H), 7.02–7.05 (m, 1H), 7.26 (t,1H), 7.32–7.38 (m, 4H), 7.43 (t, 2H), 7.55–7.63 (m, 5H), 8.22–8.24 (m,1H).

MS [(+) APCl, m/z]: 392 [M+H]⁺.

Anal. Calcd. for C₂₆H₂₁N₃O+0.04C₄H₈O₂+0.20CH₂Cl₂: C, 76.85, H, 5.31, N,10.20. Found: C, 76.99, H, 5.20, N, 9.98.

EXAMPLE 6[1,1′-Biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone

4-Biphenyl-carbonyl chloride (1.19 g) dissolved in N,N-dimethylformamide(10 mL) was added dropwise to an ice cooled solution of5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine (0.98 g) inN,N-dimethylformamide (10 mL). After stirring at room temperatureovernight, the reaction mixture was poured into water anddichloromethane. The organic layer was sequentially washed with waterand saturated sodium bicarbonate, and dried over anhydrous sodiumsulfate. The solution was filtered through a short column of Magnesol®and eluted with additional dichloromethane. The combined eluate wasrefluxed with gradual addition of hexane until incipient crystallizationoccurred. Cooling and filtration provided the title compound (0.72 g),m.p. 180–182° C.

Anal. Calcd. for C₂₆H₂₀N₂O: C, 82.95, H, 5.35, N, 7.44. Found: C, 82.84,H, 5.24, N, 7.40.

EXAMPLE 7[1,1′-Biphenyl]-4-yl-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone

[1,1′-Biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanoneof Example 6 (0.97 g) was added to sodium hydride (2 equivalents, 60% inoil, washed with hexane) and N,N-dimethylformamide (25 mL). lodomethane(0.45 g) was added and after overnight stirring, the mixture was pouredinto brine. The precipitate was collected, redissolved indichloromethane and the solution filtered through a short column ofMagnesol®. The column was rinsed with several volumes ofdichloromethane, and the combined eluate refluxed with the gradualaddition of hexane until incipient crystallization. Cooling andfiltration provided the title compound (0.89 g), m.p. 198–201° C.

MS [(+) ESI, m/z]: 391 [M+H]⁺.

EXAMPLE 8[1,1′-Biphenyl]-4-yl-(5,6,7,8-tetrahydro-thieno[3,2-b]azepin-4-yl)-methanoneStep A. 5,6,7,8-Tetrahydro-4H-thieno-[3,2-b]azepine

A solution of 6,7-dihydro-5H-benzo[b]thiophen-4-one oxime (1.67 g) indry dichloromethane (100 mL) was cooled to 0°. Following dropwiseaddition of diisobutylaluminum hydride (50 ml, 1M in hexanes), themixture was stirred at 0° for three hours and then diluted withdichloromethane (50 mL). Sodium fluoride (8.4 g) was added, followed bywater (2.7 mL). The reaction mixture was stirred vigorously for 30minutes, then filtered and concentrated to provide the title compound(0.81 g) as a white solid.

¹H-NMR (200 mHz, CDCl₃): δ 1.70 (m, 2H), 1.87 (m, 2H), 2.75 (m, 2H),3.05 (m, 2H), 3.50 (brs, 1H), 6.51 (d, 1H), 6.82 (d, 1H).

Step B.1,1′-Biphenyl-4-yl-(5,6,7,8-tetrahydro-thieno[3,2-b]azepin-4-yl)-methanone

A solution of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine of Step A(0.300 g) and N,N-diisopropylethyl amine (0.5 mL) in dichloromethane (25mL) was cooled to 0°. To this was added a solution of 4-biphenylcarbonyl chloride (0.518 g) in dichloromethane (5 ml). The solution wasstirred overnight as it warmed to room temperature, then washed with0.1N hydrochloric acid, aqueous sodium bicarbonate and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andevaporated to an oil. Flash chromatography of the residue on silica gelprovided the title compound as a white solid (0.490 g), m.p. 164–166° C.

IR (KBr, cm⁻¹): 1630

NMR (400 mHz, DMSO-d₆): δ 1.82 (br, 2H), 2.04 (br, 2H), 2.95 (dd, 2H),3.90 (br, 2H), 6.23 (br s, 1H), 6.65 (br s, 1H), 7.34, (m, 3H), 7.43,(m, 4H), 7.55 (dd, 2H).

MS [EI, m/z]: 333 [M]⁺.

Anal Calcd for C₂₁H₁₉NOS: C, 75.64, H, 5.74, N, 4.20. Found: C, 75.37,H, 5.79, N, 4.12.

EXAMPLE 9(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(6-phenyl-pyridin-3-yl)-methanone

A suspension of5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(6-chloro-pyridin-3-yl)-methanone(0.323 g) and phenyl boronic acid (0.185 g) in a mixture of toluene/1Maqueous sodium carbonate/ethanol (6 mL/2 mL/1 mL) was sparged withnitrogen for 5 minutes. To the stirred mixture was added palladium(II)acetate (0.0135 g). The reaction was then heated to reflux under astatic pressure of nitrogen for 14 hours. The suspension was dilutedwith ethyl acetate and washed with saturated aqueous sodium bicarbonateand brine. The organic layer was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to yield a green foam (0.360 g). Flashchromatography of the residue on Merck silica gel eluting with 25% ethylacetate in hexanes provided the title compound (0.250 g) as a white foamwhich was recrystallized from acetone/hexane to give yellow needles,m.p. 171–174° C.

¹H-NMR (DMSO-d₆, 400 mHz): δ 5.37 (brs, 2H), 5.92 (t, 1H), 5.97 (s, 1H),6.83 (t, 1H), 7.03 (d, 1H), 7.10 (t, 1H), 7.19 (t, 1H), 7.45 (m, 4H),7.75 (d, 1H), 7.85 (d, 1H), 8.02 (dd, 2H), 8.48 (br, 1H)

Anal Calcd for C₂₄H₁₉N₃O.0.25H₂O: C, 77.70, H, 5.31, N, 11.36. Found: C,77.70, H, 5.23, N, 11.39.

EXAMPLE 10(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(4′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)-methanone

Step A. 4′-Methoxy-3-methyl-[1,1′-biphenyl]-4-carboxylic acid

4-Bromo-2-methyl-benzoic acid (2.15 g, 10 mmol), 4-methoxy-phenylboronicacid (1.52 g, 10 mmol) and sodium carbonate (3.24 g, 30 mmol) in amixture of toluene, water and ethanol (15 mL:6 mL:3 mL) was sparged withnitrogen for 5 minutes. To this was added palladium acetate (0.014 g).The mixture was heated at reflux, under a static pressure of nitrogen,for 24 hours. The sample was diluted with water and ethyl acetate (50 mLeach) and the pH was adjusted to 1. The layers were separated and theaqueous phase was extracted with ethyl acetate. The organic extractswere combined and washed with water and brine. The sample was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresulting solid was recrystallized from ethyl acetate/hexanes to yieldthe title compound (2.16 g ) as a white solid, m.p 199–201° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.57 (s, 3H), 3.79 (s, 3H), 7.02 (m, 2H),7.21 (dd, 1H); 7.55 (s, 1H); 7.67 (m, 2H); 7.87 (d, 1H); 12.73 (s, 1H)

MS [EI, m/z]: 242 [M]⁺.

Anal. Calc'd for C₁₅H₁₄O₃: C, 74.36, H, 5.82. Found: C, 73.92, H, 5.93.

Step B.(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(4′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)-methanone

A mixture of the 4′-methoxy-3-methyl-biphenyl-4-carboxylic acid of StepA (0.486 g, 2 mmol) and thionyl chloride (3 mL) was stirred for 30minutes and then warmed to reflux for 15 minutes. The reaction productwas dissolved in toluene (10 mL) and concentrated in vacuo. This processwas repeated twice to provide the crude acid chloride. This wasdissolved in dichloromethane (10 mL) and the solution added dropwise toa cooled solution (0°) of10,11-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine (0.368 g, 2 mmol),triethylamine (0.4 mL, 2.8 mmol) and a catalytic amount of4-(dimethylamino)pyridine. The solution was stirrred overnight at roomtemperature and then quenched with 1N hydrochloric acid. The mixture wasdiluted with water and dichloromethane and the organic layer washed with0.1N hydrochloric acid, 0.1N sodium hydroxide, and water. The solutionwas dried over anhydrous sodium sulfate and concentrated to a foam. Theresidue was flash chromatographed on with 30% ethyl acetate in hexane toyield a foam (0.700 g), which upon trituration and sonication with etherand a little ethyl acetate provided the title compound (0.600 g) as awhite solid.

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.37 (s, 3H), 3.76 (s, 3H), 5.10 (br s,2H), 5.25 (br s, 2H), 5.90 (t, 1H), 5.96 (br s, 1H), 6.8–7.6 (m, 12H)

MS [(+) ESI, m/z]: 409 [M+H]⁺.

Anal. Calc'd for C₂₇H₂₄N₂O₂: C, 79.39, H, 5.92, N, 6.86. Found: C,78.51, H, 5.98, N, 6.66.

EXAMPLE 11 [1,1′-Biphenyl]-4-yl-(4H,10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone

Step A. 2-Chloromethyl-pyridine-3-carboxylic acid methyl ester

A solution of methyl 2-methylnicotinate (20.0 g, 0.132 mol) andtrichloroisocyanuric acid (46.0 g, 0.198 mol) in dichloromethane (100mL) was stirred at room temperature overnight. The reaction mixture wasthen washed with saturated aqueous sodium carbonate and saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and the solvent evaporated in vacuo to provide the titlecompound as a yellow liquid (11.2 g ), which is used as such in the nextstep.

Step B. 2-(2-Formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic acid methylester

To a suspension of sodium hydride (5.8 g, 0.12 mol), in dry N,N-dimethylformamide (25 mL) was added slowly under nitrogen a solution of pyrrole2-carboxaldehyde (10.5 g, 0.11 mol) in N,N-dimethylformamide (10 mL),and the reaction mixture was stirred at room temperature for 30 minutes.The reaction was then cooled to 5° C. and2-chloromethyl-pyridine-3-carboxylic acid methyl ester of Step A wasadded slowly, the temperature being maintained at or below 20° C. Afterthe addition was complete, the reaction was stirred at room temperaturefor 30 minutes. The mixture was evaporated to dryness, and the residuewas dissolved in ethyl acetate (250 mL). This solution was washed withwater and dried over anhydrous magnesium sulfate. The solvent was thenremoved in vacuo leaving a dark crystalline solid (23.4 g), which waspurified by chromatography on silica gel eluting with a gradient ofethyl acetate/petroleum ether to provide the title compound as a tancrystalline solid (13.75 9), m.p. 91–93° C.

Step C. [3-(2-Formyl-pyrrol-1-yl-methyl)-pyridin-2-yl]-carbamic acidbenzyl ester

To a stirred solution of2-(2-formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic acid methyl esterof Step B (13.65 g, 55.9 mmol) in methanol (50 mL) was added sodiumhydroxide (2.2 g, 55.9 mmol.). The reaction mixture was refluxed undernitrogen for 2 hours, and then the solvent was removed in vacuo. Aportion of the residual yellow solid (5 g) was suspended in a mixture ofbenzyl alcohol (20 mL) and benzene (30 mL). Diphenylphosphoryl azide(6.54 g, 1.2 equiv.) was added, and the reaction was slowly heated toreflux. After refluxing for 1 hour, the mixture was cooled and washedwith water, dried over anhydrous magnesium sulfate, filtered andevaporated to dryness to provide the title compound as a tan crystallinesolid (4.4 g), m.p. 109–111° C.

Step D. 9,10-Dihydro-4H-3a,5,9-triaza-benzo[f]azulene

A stirred mixture of[3-(2-formyl-pyrrol-1-yl-methyl)-pyridin-2-yl]-carbamic acid benzylester of step B (1.0 g), in ethyl acetate (10 mL) containing 10%palladium on charcoal (10 mg.), magnesium sulfate (0.010 g) and 5 dropsof acetic acid was hydrogenated at atmospheric pressure until hydrogenuptake ceased. The reaction mixture was then filtered through Celite andthe solvent removed in vacuo. The crude product (yellow crystallinesolid, 0.530 g) was purified by chromatography on silica gel elutingwith a gradient of ethyl acetate in petroleum ether to provide the titleproduct as a yellow crystalline solid, m.p. 171–172° C.

Step E.1,1′-Biphenyl-4-yl-(4H,10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone

A stirred mixture of 9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene ofStep D (0.54 mmol), 4-phenylbenzoylchloride (1.08 mmol) andtriethylamine (1.08 mmol) in toluene was refluxed under nitrogen for 72hours. The reaction was cooled and the solvent removed in vacuo.Chromatography of the residue over silica gel Merck-60 with a solventgradient from 5 to 20% ethyl acetate in hexane provided the titlecompound as a tan solid.

¹H-NMR (DMSO-d₆, 400 MHz): δ 5.1 (bs, 2H), 5.4 (s, 2H), 5.9 (m, 1H), 6.0(s, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.3–8.7 (m, 10H), 8.3 (m, 1H).

MS [APCI, m/z]: 366 [M+H]⁺.

Anal. Calcd. for C₂₄H₁₉N₃O+0.5H₂O: C, 76.99, H, 5.38, N, 11.22. Found:C, 77.28, H, 5.22, N, 10.71.

The following examples were prepared according to the General ProcedureA described below.

General Procedure A

Step A. An optionally substituted haloaryl carboxylic acid (1.1 mol) wasconverted to the acid chloride by treatment with oxalyl chloride (1.5mmol) and a catalytic amount of N,N-dimethylformamide indichloromethane. Upon consumption of the acid as determined by HPLCanalysis, all volatiles were removed in vacuo. The residue was dissolvedin dichloromethane and added dropwise to a stirred and cooled (0° C.)solution of an appropriately substituted10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine,11-methyl-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine, or5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine (1 mmol)respectively, and N,N-diisopropylethyl amine (1.2 mmol) indichloromethane. After 1–16 hours, the mixture was diluted withdichloromethane and washed with 10% aqueous sodium bicarbonate. Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered and concentrated.

Step B. To the residue was added an appropriately substitutedarylboronic acid (1.2 mmol), potassium carbonate (2.5 mmol),tetrabutylammonium bromide (1 mmol), palladium(II)acetate (3% mole) andwater/acetonitrile (1:1.2 mL). The mixture was heated at 70° C. for 1.5hours, then ethyl acetate was added and the organic phase washed withwater. The solution was filtered through a small plug of Celite andconcentrated to dryness.

EXAMPLE 12[3-Chloro-2′-methyl-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 439.15770 [M+H]⁺. Calcd. for C₂₈H₂₄ClN₂O:439.15716.

EXAMPLE 13[3-Chloro-2′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 455.15195 [M+H]⁺. Calcd. for C₂₈H₂₄ClN₂O₂:455.15208.

EXAMPLE 14[3-Chloro-3′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 455.15195 [M+H]⁺. Calcd. for C₂₈H₂₄ClN₂O₂:455.15208.

EXAMPLE 15[2′-Methyl-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 405.19555 [M+H]⁺. Calcd. for C₂₈H₂₅N₂O: 405.19614.

EXAMPLE 16[2′-Methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 421.19021 [M+H]⁺. Calcd. for C₂₈H₂₅N₂O₂: 421.19106.

EXAMPLE 17[3′-Methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 421.19067 [M+H]⁺. Calcd. for C₂₈H₂₅N₂O₂: 421.19106.

EXAMPLE 18[3-Chloro-2′-methyl-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone

HRMS [(+) ESI, m/z]: 440.15163 [M+H]⁺. Calcd. for C₂₇H₂₃ClN₃O:440.15241.

EXAMPLE 19[3-Chloro-2′-methoxy-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone

HRMS [(+) ESI, m/z]: 456.14731 [M+H]⁺. Calcd. for C₂₇H₂₃ClN₃O₂:456.14732.

EXAMPLE 20[3-Chloro-3′-methoxy-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone

HRMS [(+) ESI, m/z]: 456.14687 [M+H]⁺. Calcd. for C₂₇H₂₃ClN₃O₂:456.14732.

EXAMPLE 21[2′-Methyl-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone

HRMS [(+) ESI, m/z]: 406.19025 [M+H]⁺. Calcd. for C₂₇H₂₄N₃O: 406.19139.

EXAMPLE 22[2′-Methoxy-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone

HRMS [(+) ESI, m/z]: 422.18706 [M+H]⁺. Calcd. for C₂₇H₂₄N₃O₂: 422.18631.

EXAMPLE 23[3′-Methoxy-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone

HRMS [(+) ESI, m/z]: 422.18617 [M+H]⁺. Calcd. for C₂₇H₂₄N₃O₂: 422.18631.

EXAMPLE 24[3-Chloro-2′-methyl-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 413.14172 [M+H]⁺. Calcd. for C₂₆H₂₂ClN₂O:413.14151.

EXAMPLE 25[3-Chloro-2′-methoxy-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 429.13611 [M+H]⁺. Calcd. for C₂₆H₂₂ClN₂O₂:429.13643.

EXAMPLE 26[3-Chloro-3′-methoxy-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 429.13622 [M+H]⁺. Calcd. for C₂₆H₂₂ClN₂O₂:429.13643.

EXAMPLE 27[2′-Methyl-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 379.17963 [M+H]⁺. Calcd. for C₂₆H₂₃N₂O: 379.18049.

EXAMPLE 28[2′-Methoxy-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 395.17496 [M+H]⁺. Calcd. for C₂₆H₂₃N₂O₂: 395.17541.

EXAMPLE 29[3′-Methoxy-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

HRMS [(+) ESI, m/z]: 395.17529 [M+H]⁺. Calcd. for C₂₆H₂₃N₂O₂: 395.17541.

1. A compound of formula:

wherein: R is C₃–C₆ alkyl; R₃, R₆, R_(3′), and R_(5′) are independentlyselected from the group consisting of H, C₁–C₆ alkyl, halogen, cyano,CF₃, hydroxy, C₁–C₆ alkoxy, C₁–C₆ alkoxy carbonyl, carboxy, —CONH₂,—CONH[C₁–C₆ alkyl], and —CON[C₁–C₆ alkyl ]₂; and R₂, R₇, R₈ and R₉ areeach, independently, selected the group consisting of hydrogen, C₁–C₃alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃, and CN: and or apharmaceutically acceptable salt or prodrug form thereof.
 2. A method oftreating diabetes insipidus, nocturnal enuresis, nocturia, urinaryincontinence, or hemophilia, or inducing temporary delay of urination ina mammal in need thereof, the method comprising administering to themammal a pharmaceutically effective amount of a compound of formula:

wherein: R is hydrogen or C₁–C₆ alkyl; R₃, R₅, R_(3′), and R_(5′)independently selected from the group consisting of H, C₁–C₆ alkyl,halogen, cyano, CF₃, hydroxy C₁–C₆ alkoxy, C₁–C₆ alkoxy carbonyl,carboxy, —CONH₁, —CONH[C₁–C₆ alkyl], and —CON[C₁–C₆ alkyl]₂; R₂, R₇, R₈and R₉ are each, independently, selected the group consisting ofhydrogen, C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃, and CN; andor a pharmaceutically acceptable salt or prodrug form thereof.
 3. Themethod of claim 2 wherein said compound is[1,1-biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 4. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable carrier.
 5. The method ofclaim 2 wherein said compound is[1,1-biphenyl]-4-yl-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 6. The method ofclaim 2 wherein said compound is[3-chroro-2′-methyl-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 7. The method ofclaim 2 wherein said compound is[3-chloro-2′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 8. The method ofclaim 2 wherein said compound is[3-chloro-3′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 9. The method ofclaim 2 wherein said compound is[2′-methyl-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 10. The method ofclaim 2 wherein said compound is[2′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone, or apharmaceutically acceptable salt form thereof.
 11. The method of claim 2wherein said compound is[3′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 12. A compound offormula:

wherein: R is hydrogen or C₁–C₆ alkyl; R₃, R₅, R_(3′), and R_(5′) areindependently selected from the group consisting of H, C₁–C₆ alkyl,halogen, cyano, CF₃, hydroxy, C₁–C₆ alkoxy, C₁–C₆ alkoxy carbonyl,carboxy, —CONH₂, —CONH[C₁–C₆ alkyl], and —CON[C₁–C₆ alkyl]₂; and R₂, R₇,R₈ and R₉ are each, independently, selected the group consisting ofhydrogen, C₁–C₆ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃, and CN; ora pharmaceutically acceptable salt or prodrug form thereof.
 13. Apharmaceutical composition comprising a pharmaceutically effectiveamount of a compound of claim 12 and a pharmaceutically acceptablecarrier.
 14. A compound of formula:

wherein: R is C₁–C₆ alkyl; R₃, R₅, R_(3′), and R_(5′) are independentlyselected from the group consisting of H, C₁–C₆ alkyl, halogen, cyano,CF₃, hydroxy, C₁–C₆ alkoxy, C₁–C₆ alkoxy carbonyl, carboxy, —CONH₂,—CONH[C₁–C₆ alkyl], and —CON[C₁–C₆ alkyl]₂; R₂ is selected from thegroup consisting of C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃,and CN; and R₇, R₈ and R₉ are each, independently, selected the groupconsisting of hydrogen, C₁–C₆ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃,SCF₃, and CN; or a pharmaceutically acceptable salt or prodrug formthereof.
 15. The compound of claim 14 wherein said compound is[3-chloro-2′-methyl-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 16. The compound ofclaim 14 wherein said compound is[3-chloro-2′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 17. The compound ofclaim 14 wherein said compound is[3-chloro-3′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 18. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof claim 14 and a pharmaceutically acceptable carrier.
 19. A compound offormula:

wherein: R is C₁–C₆ alkyl; R₃, R₅, R_(3′), and R_(5′) are independentlyselected from the group consisting of H, C₁–C₆ alkyl, halogen, cyano,CF₃, hydroxy, C₁–C₆ alkoxy, C₁–C₆ alkoxy carbonyl, carboxy, —CONH₂,—CONH[C₁–C₆ alkyl], and —CON[C₁–C₆ alkyl]₂; R₇ is selected from thegroup consisting of C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃,and CN; and R₂, R₈ and R₉ are each, independently, selected the groupconsisting of hydrogen, C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃,SCF₃, and CN; or a pharmaceutically acceptable salt or prodrug formthereof.
 20. The compound of claim 19 wherein said compound is[2′-methyl-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 21. The compound ofclaim 19 wherein said compound is[2′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-diazepin[b,e][1,4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 22. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof claim 19 and a pharmaceutically acceptable carrier.
 23. A compound offormula:

wherein: R is C₁–C₆ alkyl; R₃, R₅, R_(3′), and R_(5′) are independentlyselected from the group consisting of H, C₁–C₆ alkyl, halogen, cyano,CF₃, hydroxy, C₁–C₆ alkoxy, C₁–C₆ alkoxy carbonyl, carboxy, —CONH₂,—CONH[C₁–C₆ alkyl], and —CON[C₁–C₆ alkyl]₂; R₈ is selected from thegroup consisting of C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃,and CN; and R₂, R₇ and R₉ are each, independently, selected the groupconsisting of hydrogen, C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃,SCF₃, and CN; or a pharmaceutically acceptable salt or prodrug formthereof.
 24. The compound of claim 23 wherein said compound is[3-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][4]diazepin-10-yl)methanone,or a pharmaceutically acceptable salt form thereof.
 25. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof claim 23 and a pharmaceutically acceptable carrier.
 26. A compound offormula:

wherein: R is C₁–C₆ alkyl; R₃, R₅, R_(3′), and R_(5′) are independentlyselected from the group consisting of H, C₁–C₆ alkyl, halogen, cyano,CF₃, hydroxy, C₁–C₆ alkoxy, C₁–C₆ alkoxy carbonyl, carboxy, —CONH₂,—CONH[C₁–C₆ alkyl], and —CON[C₁–C₆ alkyl]₂; R₉ is selected from thegroup consisting of C₁–C₆ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃, SCF₃,and CN; and R₂, R₇ and R₈ are each, independently, selected the groupconsisting of hydrogen, C₁–C₃ alkyl, OCH₃, halogen, CF₃, SCH₃, OCF₃,SCF₃, and CN; or a pharmaceutically acceptable salt or prodrug formthereof.
 27. A pharmaceutical composition comprising a pharmaceuticallyeffective amount of a compound of claim 26 and a pharmaceuticallyacceptable carrier.